Incidence
Non Hodgkin's lymphoma was the tenth most commonly diagnosed malignancy in Australia in 2010.[1] Hodgkin lymphoma (HL) comprises approximately 10% of lymphomas and 0.6% cancers worldwide.
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Classification of haematopoietic and lymphoid malignancies
Various classifications have been used in older literature sources, however in current usage is the World Health Organization (WHO) classification of 2001, updated in 2008. This incorporated the new knowledge of both immunophenotypic and cytogenetic information.[2] The focus is on lineage derivation into myeloid, lymphoid or dendritic/histiocytic entities, though there is sometimes biphenotypic differentiation or “lineage infidelity”, suggesting derivation from multipotent progenitor cells.[3]
| Myeloid:
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- acute myeloid leukaemias (of various subtypes, AML) with >20% blasts in marrow or peripheral blood, or specific genetic abnormalities. Recurring genetic abnormalities, myelodysplastic features or extraosseous tissue deposits of “myeloid sarcoma”.
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- myeloproliferative neoplasms (MPN) including chronic myeloid leukaemia, essential thrombocythaemia, polycythaemia vera, chronic neutrophilic leukaemia, chronic eosinophilic leaukaemia, mastocytosis and primary myelofibrosis
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- myelodysplastic syndromes (MDS) including <20% blasts and unilineage or multilineage dysplasia, specific recurring chromosomal abnormalities and childhood MDS.
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AML is inevitably aggressive in its course and needs immediate therapy. It may be a primary or secondary neoplastic change, consequent on a prior immunological or haematological disturbance or therapy (eg prior chemotherapy or radiation).
There may be an overlap between MPN and MDS and the course is very variable, but may evolve to AML.
| Lymphoid:
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- Previous segregation of mass disease (lymphoma) vs bone marrow/blood involvement (leukaemia) has been relaxed, as there may be an evolution either way.
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- There may be a clinical segregation into 3 groups according to “indolent” (35-40% patients) vs “aggressive” vs “highly aggressive” (5% patients) behaviour of B or T cell neoplasms, with Hodgkins lymphoma being classified separately.[4]
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- Highly aggressive histologies include precursor B or T lymphoblastic leukaemia/lymphomas and Burkitt lymphoma/leukaemia, (which may have a relationship to EBV infection, endemic in African populations, but also be sporadic or related to immunodeficiency in HIV and other groups).
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- Intermediate and mature lymphoproliferative disorders (LPD) with histologies which are more variable in their clinical behaviour, including B and T cell derivation, and with potential immune phenomena in B cell types affecting their clinical behaviour and the need to treat rather than monitor. These include plasma cell neoplasms such as plasmablastic lymphoma (HIV associated) and plasma cell plasmacytoma/myeloma, mature B cell neoplasms including follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma (“Waldenstrom’s macroglobulinaemia”), mantle cell lymphoma, prolymphocytic lymphoma and diffuse large B cell lymphoma (comprising 25% of cases of NHL, the most common entity).
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- Hodgkin lymphoma (HL) is unique in that the malignant cells are the minority (Reed-Sternberg cells or variants derived from germinal centre cells) in an inflammatory background. There are two main subtypes of nodular lymphocyte predominant HL and “classical HL” including nodular sclerosis subtype, mixed cellularity (+/- EBV), lymphocyte depleted (EBV+/-) and lymphocyte rich HL. Bimodal age distribution (20s and >70s).
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- Mature T cell or natural killer (NK) cell lineage, including circulating disease, mass disease and cutaneous variants, with very variable presentations and natural history.
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| Histiocytic/dendritc neoplasms:
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- Uncommon primary presentations of antigen presenting cells (APC) and connective tissue macrophages (histiocytes).
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- Generally grouped into the “Langerhans cell histiocytoses”
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Background history
Connective tissue disorders as precursors for a secondary LPD. Also some increased risk in family members for HL. Environmental exposures and past chemotherapy or radiotherapy as risk factors for a secondary leukaemia.
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Common presentations
Leukaemia
| Cytopenia:
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- anaemia (marrow infiltration or haemolysis)
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- neutropenia with bacterial and fungal infections
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- thrombocytopenia and bleeding manifestations such as gum bleeding, petechial rash or ecchymoses, hollow organ or intracranial bleeding.
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- hyperviscosity symptoms (especially IgM paraprotein of Waldenstroms macroglobulinaemia and very high WCC in ALL)
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- Mass organ involvement with hepatosplenomegaly, CNS involvement, obstructive complications (spinal cord, GIT, ureter, bronchus)
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- Coagulopathy incl. disseminated intravascular coagulation (esp. with acute promyelocytic leukaemia).
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Lymphoma
Risk factors include HIV/EBV/ HCV infection, family history of lymphoprolferative disorder (LPD), background autoimmune disorders for secondary lymphoproliferative disorder, inflammatory gastrointestinal disease (e.g. Crohn’s disease, coeliac disease, Helicobacter pylori chronic gastritis), environmental exposures (see Table 2).[5]
| Mass disease:
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- “lumps and bumps”, typically painless unlike inflammatory causes hepatosplenomegaly)
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- obstruction of hollow organ, e.g. bronchus, ureter, CBD
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- NS symptoms (CNS, brainstem, cord, nerve root)
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- cutaneous rash, effusion (pleural/pericardial/peritoneal)
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- cytopenia due to marrow infiltration
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- Waldeyer’s ring, ocular apparatus
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| Constitutional disturbance:
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- fatigue/drenching sweats/fevers >38º
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- weight loss >10% body weight in 6mth
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- known as “B symptoms” (originally described in HL).
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| Metabolic disturbance:
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- hypercalcaemia, hyperuricaemia, renal impairment, hyperviscosity associated with IgM paraproteinaemia (Waldenstroms macroglobulinaemia.)
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- elevated lactate dehydrogenase (in aggressive histologies and with high tumour burden)
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| Immune phenomena:
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- primary haemolysis/thrombocytopenia, less commonly neutropenia (potentially associated with splenomegaly)
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- angioedema associated with acquired C1 esterase inhibitor deficiency
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| Paraneoplastic phenomena:
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- neurological, metabolic, cutaneous presentations are rare.
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Myeloma
| Cytopenia:
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- anaemia, neutropenia, thrombocytopenia
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- “reciprocal”hypogammaglobulinaemia and infection tendency
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| Mass disease:
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- bone pain/destructive (marrow bearing) lytic bone lesions
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- vertebral destruction and cord compromise or radiculopathy
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| Metabolic disturbance:
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- hyperviscosity (especially multimers of IgA)
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- renal impairment (due to above as well as light chain deposition and tubular casts, concurrent light chain amyloidosis)
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- constitutional disturbance (weight loss, fevers, fatigue)
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| Coincidental finding:
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- Elevated total serum protein
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- Elevated total serum protein
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- Urinalysis showing proteinuria
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- Paraprotein estimation by electrophoresis of serum (IgG/A/D {rare}with kappa or lambda light chains, or free kappa or lambda light chains only in up to 20%.) Approx. 5% truly nonsecretory of immunoglobulin or free light chains and with no histochemical staining in plasma cells.
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- Renal biopsy may show waxy, laminated casts and renal amyloidosis.
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Definitive diagnosis
Biopsy
Fine needle aspiration cytology may help define broad lymph node pathology, but architectural features and more cellular material obtained by an excision biopsy allows full classification. Cytogenetics, flow cytometry and gene rearrangements aid subclassification.
Bone marrow examination is routine and CSF may be sampled, especially in aggressive lymphoma histologies such as Burkitt’s lymphoma and leukaemia/lymphoma, where it may be a “sanctuary site” for later relapse, as may be the testes.
Bone marrow aspiration and trephine biopsy are essential to definitively diagnose myeloma and differentiate it from monoclonal gammopathy of undetermined significance (MGUS).
Staging
Staging the extent of both NHL and HL is based on Ann Arbor classification Table 3, Ref. 4) as determined by physical findings, CT, MRI and PET scan findings (see LN location Figure 1).[5] In addition, risk stratification is assisted by use of the Revised International Prognostic Index (R-IPI) and follicular lymphoma prognostic index (FLIPI) (see Table 3[6] and Table 4[7]).
Myeloma assessment is by skeletal survey to determine the volume of lytic disease in marrow bearing bones, checking for end-organ damage in the form of hypercalcaemia/anaemia/renal failure, determining the burden of disease related to paraprotein concentration (Durie and Salmon system 1975 and Table 5).[8]
Serum and urine (Bence Jones) electrophoresis and immunofixation
| Management:
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- It is important to determine if a NHL is CD20+ where potential immune therapy with rituximab, a monoclonal antibody against the “cluster determinant 20”, has importance in both indolent and diffuse large cell lymphomas. (Hence “R-IPI” rather than earlier “IPI”, predating “the rituximab era”.)
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- If indolent histology NHL, potentially “watch and wait” unless bulk of disease and compromise to organ function (eg ureteric obstruction with retroperitoneal mass), immune phenomena or cytopenia due to marrow involvement dictate intervention.
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- Otherwise usually systemic chemotherapy for “intermediate” and “aggressive” histologies of NHL and HL, with multi-agent protocols, unless Stage 1 disease, able to be encompassed in a radiation field and potentially curable with localised therapy.
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- In myeloma, host demographic factors, stage and cytogenetic/FISH profile help to determine the appropriate systemic therapy protocol and/or autograft eligibility. Cytotoxics (especially alkylating agents), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitor (bortezomib) and importantly corticosteroid are options.
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| Prognosis:
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- Therapy for chronic and acute leukaemias is very complex and beyond the scope of the chapter, but includes cytotoxic chemotherapy, immunomodulatory therapy, tyrosine kinase inhibitors, progenitor cell autograft and allograft (sibling donor and matched unrelated donor).
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- Intermediate and aggressive NHL and HLmay be {potentially} curable but control is the aim in indolent forms, unless Stage 1, when systemic dissemination may not have yet occurred and local therapy may suffice.
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- Myeloma is controlled, by systemic therapy with or without a progenitor cell autograft, but only cure may be achieved with an allograft, sadly at high risk of fatal complications.
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References
- ↑ Australian Institute of Health and Welfare. Cancer in Australia: key facts. [homepage on the internet] Canberra: AIHW; 2013 [cited 2014 May 22; updated 2013]. Available from: http://www.aihw.gov.au/cancer/cancer-in-australia/.
- ↑ Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H. WHO classification of tumours of haematopoietic and lymphoid tissues, fourth edition. Lyon, France: IARC; 2008 [cited 2014 May 22] Available from: http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1&codcol=70&codcch=4002.
- ↑ Freedman AS, Friedberg JW, Aster JC. Classification of the hematopoietic neoplasms. [serial online]: UpToDate; 2013 Sep 9 [cited 2014 May 22] Available from: http://www.uptodate.com/contents/classification-of-the-hematopoietic-neoplasms?source=search_result&search=Classification+of+the+hematopoietic+neoplasms&selectedTitle=1~150.
- ↑ Aster JC. Epidemiology, pathologic features, and diagnosis of classical Hodgkin lymphoma. [serial online]: UpToDate; 2014 Jan 14 [cited 2014 May 22] Available from: http://www.uptodate.com/contents/epidemiology-pathologic-features-and-diagnosis-of-classical-hodgkin-lymphoma.
- ↑ 5.0 5.1 Freedman AS, Friedberg JW, Aster JC. Clinical presentation and diagnosis of non-Hodgkin lymphoma. [serial online]: UpToDate; 2014 Feb 24 [cited 2014 May 22] Available from: http://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-non-hodgkin-lymphoma?source=search_result&search=Clinical+presentation+and+diagnosis+of+non-Hodgkin+lymphoma&selectedTitle=1~150.
- ↑ Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007 Mar 1;109(5):1857-61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17105812.
- ↑ Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular lymphoma international prognostic index. Blood 2004 Sep 1;104(5):1258-65 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15126323.
- ↑ Rajkumar SV. Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. [serial online]: UpToDate; 2014 Apr 4 [cited 2014 May 22] Available from: http://www.uptodate.com/contents/clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma?source=search_result&search=Rajkumar+SV.+Clinical+features%2C+laboratory+manifestations%2C+and+diagnosis+of+multiple+myeloma&selectedTitle=2~150.
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